title: Enhancing VSV oncolytic activity with an improved cytosine deaminase suicide gene strategy.
abstract: Oncolytic viruses (OVs) are promising therapeutic agents for cancer treatment, with recent studies emphasizing the combined use of chemotherapeutic compounds and prodrug suicide gene strategies to improve OV efficacy. In the present study, the synergistic activity of recombinant vesicular stomatitis virus (VSV)-MΔ51 virus expressing the cytosine deaminase/uracil phosphoribosyltransferase (CD::UPRT) suicide gene and 5-fluorocytosine (5FC) prodrug was investigated in triggering tumor cell oncolysis. In a panel of VSV-sensitive and -resistant cells-prostate PC3, breast MCF7 and TSA, B-lymphoma Karpas and melanoma B16-F10-the combination treatment increased killing of non-infected bystander cells in vitro via the release of 5FC toxic derivatives. In addition, we showed a synergistic effect on cancer cell killing with VSV-MΔ51 and the active form of the drug 5-fluorouracil. Furthermore, by monitoring VSV replication at the tumor site and maximizing 5FC bioavailability, we optimized the treatment regimen and improved survival of animals bearing TSA mammary adenocarcinoma. Altogether, this study emphasizes the potency of the VSV-CD::UPRT and 5FC combination, and demonstrates the necessity of optimizing each step of a multicomponent therapy to design efficient treatment.
authors.affiliation: Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Quebec, Canada.
authors.forename: S
authors.initials: S
authors.lastname: Leveille
authors.forename: S
authors.initials: S
authors.lastname: Samuel
authors.forename: M-L
authors.initials: ML
authors.lastname: Goulet
authors.forename: J
authors.initials: J
authors.lastname: Hiscott
mesh_terms: D003131:Combined Modality Therapy; D043525:Cytosine Deaminase / Q000235:genetics*; D005437:Flucytosine / Q000494:pharmacology; D005472:Fluorouracil / Q000494:pharmacology; D041722:Genes, Transgenic, Suicide; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D050504:Oncolytic Viruses / Q000235:genetics* / Q000378:metabolism; D010430:Pentosyltransferases / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics; D018116:Vesiculovirus / Q000235:genetics* / Q000378:metabolism
chemical_list: D011993:Recombinant Fusion Proteins; D005437:Flucytosine; D010430:Pentosyltransferases; C023269:uracil phosphoribosyltransferase; D043525:Cytosine Deaminase; D005472:Fluorouracil